Mycobacterium tuberculosis (Mtb) continues to cause significant morbidity and mortality worldwide. TB in the elderly can arise directly from a new infection, reflecting the documented general increase in susceptibility of the elderly to numerous infections including Mtb, or reactivate from a previously latent Mtb infection, and is frequently attributed to deficits in adaptive immune function. However, little experimental information exists to define the specific aspects of immune dysfunction that contribute to the increased susceptibility of the elderly to Mtb infection. There are numerous changes in central immune function (thymus production of T cells), peripheral T cell repertoire and functional parameters, and in the peripheral environment (e.g. increased inflammatory conditions) with aging, any or all of which could contribute to the increased risk for active Mtb infection in the elderly. However, each of these mechanisms would be best approached therapeutically in different ways. Thus, our long-term goal is to identify the specific contributions of these immune changes to increased rates of Mtb infection in the elderly and develop effective treatment strategies. In this proposal, we will use unique mouse genetic resources developed in the Manley lab to test two hypotheses: that this innate-like TEM subpopulation plays a critical role in controlling Mtb infection and establishing latency, and that time since thymic involution plays a significant role in enhanced rates of Mtb primary infections and latency reactivation in the elderly. In Aim 1 we will determine whether innate-like TEM peripheral T cells can enhance the immune response to primary Mtb infection, using the Foxn1?/? mouse model and in vitro and in vivo assays. In Aim 2 we will test whether enhanced disease progression and severity of active Mtb infection in the elderly is due to changes in the peripheral T cell pool caused by thymic involution, or by the physiological effects of aging using Foxn1Z/Z mice that undergo premature thymic involution. These studies may provide new insights into the T cell mechanisms regulating Mtb infection in the elderly, and define new mouse models that may be useful for the study of the immune response to Mtb infection.